Entry of enveloped animal viruses requires fusion between the viral membrane and a cellular membrane, either the plasma membrane or an internal membrane. Class I fusion proteins possess a “fusion peptide” at or near the amino terminus, a pair of extended alpha helices and, generally, a cluster of aromatic amino acids proximal to a hydrophobic transmembrane anchoring domain (Carr and Kim, 1993; Suarez et al., 2000; Wilson, Skehel, and Wiley, 1981). Several otherwise disparate viruses, including orthomyxoviruses, paramyxoviruses, retroviruses, arenaviruses, and filoviruses encode class I fusion proteins varying in length and sequence, but highly similar in overall structure (Gallaher, 1996; Gallaher et al., 1989). X-ray crystallography of the E glycoprotein (E-protein) of tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus of the Flaviviridae family, revealed a structure for this fusion protein distinct from other fusion proteins (Rey et al., 1995). E-protein possesses an internal fusion peptide stabilized by dicysteine linkages and three domains (I-III) comprised mostly of antiparallel beta sheets. In the slightly curved rod-like configuration of the E-protein present in the virion, the fusion peptide is located at the tip of domain II, the furthest point distal from the C-terminal transmembrane anchor. Examination by Lescar and coworkers (2001) of E1, the fusion protein of the Togavirus Semliki Forest virus (SFV), revealed a remarkable fit to the scaffold of TBEV E. Recently, the E-glycoprotein of dengue virus, a medically important Flavivirus, was also shown to have a class II structure (Kuhn et al., 2002).
The Flaviviridae family consists of three genera, Flaviviruses, hepaciviruses and pestiviruses. In the United States alone, 4 million people are infected with a member of the hepacivirus genus, hepatitis C virus (HCV). This is four times the number infected by HIV. Each year in the US, 30-50,000 new HCV infections occur, and about 15-20,000 people die. These numbers are expected to increase dramatically. The infection is spread primarily through needle sharing among drug users, although there is some risk from accidental needle sticks, blood products before 1992, chronic blood dialysis, and frequent sexual contact. Current treatments for HCV using ribavirin and interferon cost $8,000 to $20,000 per year, and help about half of patient only partly. End stage HCV disease is the most frequent indication for liver transplants and this costs $250,000 to $300,000. Better drugs to treat HCV infection and an effective vaccine to prevent HCV infection are urgently needed. Members of the Flavivirus genus, dengue virus, Japanese encephalitis virus, yellow fever virus, and West Nile virus, cause important human diseases world-wide. Pestiviruses, such as bovine viral diarrhea virus and border disease virus, cause significant veterinary illnesses.